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Voltage-coupled conformational dynamics of mitochondrial protein-import channel

Nature Structural & Molecular Biology volume 20, pages 915–917 (2013)Cite this article

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Mitochondria contain multisubunit translocases to import preproteins from the cytosol. The presequence translocase of the inner membrane operates in a voltage-gated manner, but how a preprotein-conducting channel responds to the membrane potential was unknown. A new study identifies a voltage-coupled conformational change in a transmembrane segment of the Tim23 import channel, representing a major step toward understanding the molecular basis of a voltage-gated protein translocase.

Protein translocation across the mitochondrial inner membrane is a complicated multistep process. Preprotein transfer from TOM to TIM23 involves the outer-membrane receptor Tom22, the inner-membrane receptor Tim50 and the regulatory protein Tim21. Upon passage of the preprotein through the TOM complex, the presequence binds the intermembrane-space domain of Tom22, whereas the mature part of the preprotein is in proximity to Tim50 (Fig. 2c)6. Tim21 facilitates the transfer of preproteins to Tim50, and Tim50 forms the preprotein (presequence) receptor of the TIM23 complex together with the intermembrane-space domain of the Tim23 protein7,8,9,10,11,12,13. The preprotein inserts into the protein-conducting channel of the TIM23 complex, driven by the directional movement of the positively charged presequence in the electrical field across the inner membrane, which is negative on the matrix side (Fig. 2d). ΔΨ is the only required energy source for the lateral membrane insertion of preproteins that contain a hydrophobic stop-transfer segment after the positively charged matrix-targeting signal (Fig. 2e)14. For translocation of water-soluble preproteins into the matrix, ATP hydrolysis is required as an additional energy source. The membrane-embedded core of the TIM23 machinery associates with the presequence translocase–associated import motor (PAM), which contains the mitochondrial heat-shock protein 70 (mtHsp70) as an ATP-fueled force-generating device (Fig. 2f)3,4,11,15,16.

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Figure 1: The mitochondrial machinery for import of preproteins with positively charged presequences.
Figure 2: Molecular mechanism of the presequence translocase of the inner mitochondrial membrane (hypothetical model).

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Acknowledgements

We thank M. Bohnert and C. Mehnert for discussion. This work was supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 746 and the Excellence Initiative of the German Federal and State Governments (EXC 294 BIOSS).

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  1. Martin van der Laan, Sandra G. Schrempp and Nikolaus Pfanner are at the Institut für Biochemie und Molekularbiologie, Zentrum für Biochemie und Molekulare Zellforschung, and the BIOSS Centre for Biological Signalling Studies, Universität Freiburg, Freiburg, Germany.,

    Martin van der Laan, Sandra G Schrempp & Nikolaus Pfanner

  2. Sandra G. Schrempp is also at the Fakultät für Biologie, Universität Freiburg, Freiburg, Germany.,

    Sandra G Schrempp

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van der Laan, M., Schrempp, S. & Pfanner, N. Voltage-coupled conformational dynamics of mitochondrial protein-import channel. Nat Struct Mol Biol 20, 915–917 (2013). https://doi.org/10.1038/nsmb.2643

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